Regulation of the sexually dimorphic growth of skeletal muscle by the GH/IGF-1/Myostatin axis and gonadal steroids

Abstract

The growth of skeletal muscles is sexually dimorphic in both rodents and humans, with growth being greater in males and females. Sexually dimorphic growth was initially attributed to opposing actions of gonadal steroids (androgens and estrogens), whereby androgens stimulate growth and estrogens inhibit growth. Subsequent studies have shown that sexually dimorphic growth is primarily regulated by growth hormone (GH), which regulates expression of insulin-like growth factor-one (IGF-1) and myostatin (Mstn) in skeletal muscle through the intracellular signalers Stat5a and Stat5b. Consequently, sexually dimorphic growth has been attributed to interactions between gonadal steroids and the GH/IGF-1/Mstn axis, particularly signaling of Stat5b. However, the nature of these interactions and the precise roles of both Stat5a and Stat5b in skeletal muscle are poorly understood. In vivo and in vitro studies in this thesis show that androgens and estrogens both have direct anabolic actions on skeletal muscle, but via different and often opposing mechanisms. Androgens increase GH-induced signaling of Stat5b and both the expression and signaling of IGF-1, whilst reducing the expression of Mstn. In contrast, estrogens inhibit GH-induced signaling of Stat5b and activate downstream signaling of IGF-1, independently of expression of IGF-1 or Mstn. GH potentiates signaling of androgens, estrogens and IGF-1 in skeletal muscle by increasing expression of their receptors. Stat5a and Stat5b are shown to have both individual and redundant roles, whilst likely inhibiting each other, in mediating the signaling of GH in skeletal muscle. Furthermore, Stat5a and Stat5b are shown to have essential roles in regulating myogenesis and the actions of gonadal steroids and IGF-1 in skeletal muscle, which are independent to their roles in GH signaling. These results demonstrate that androgens and estrogens have contrasting and often opposing interactions with each component of the GH/IGF-1/Mstn axis in skeletal muscle. These data also suggest that crosstalk between signaling of GH and both IGF-1 and gonadal steroids is even more complex than previously thought. By characterising the interactions between gonadal steroids and the GH/IGF-1/Mstn axis and determining the roles of Stat5a and Stat5b in skeletal muscle, these studies have greatly improved our understanding of the mechanisms that regulate sexually dimorphic growth.